tbuckley/cabot-search huggingface dataset:
Prognostic significance of pleural effusion exhausted CD8+ T cell subsets in non-small cell lung cancer and mesothelioma.
Authors: Linda Ye, Ian Dick, Peter Chiang, Tina Firth, Jenette Creaney, Bruce WS Robinson, Alec Redwood
Journal: Journal of Clinical Oncology (2022)

e21111 Background: Following repeated tumor antigen stimulation, T cells lose functional capacity and become exhausted. T cell exhaustion is a progressive change in phenotype. Early in the pathway, stem-like exhausted T cells (Tex stem ) retain proliferative and cytotoxic potential. However, they differentiate into terminally exhausted T cells (Tex term ) that become epigenetically fixed in a suppressed state and lose much of their effector function. Malignant pleural effusion is a peri-tumoral microenvironment that could offer insight into anti-tumor immune responses. In this study we characterized exhausted CD8+ T cells, examined the prognostic significance of Tex stem and Tex term levels in the pleural effusions of patients with non-small cell lung cancer (NSCLC) and validated our findings in a mesothelioma cohort. Methods: Pre-treatment malignant pleural effusions from 43 NSCLC (41 non-squamous and 2 squamous) and 50 mesothelioma patients were analyzed by flow cytometry. The percentages of Tex stem (PD1 mid CD39 - or PD1 mid CD39 - CD28 + ) and Tex term (PD1 hi CD39 + ) CD8+ T cells were correlated with overall survival (OS). Survival analysis was performed using Kaplan-Meier and multivariate Cox regression analysis adjusting for age, sex, histological and molecular subtypes, performance status, smoking history, comorbidities and the number of lines of systemic therapy. Results: The relative percentages of exhausted T cells within the CD8+ T cell compartment of pleural effusions from NSCLC and mesothelioma were similar (Table). In NSCLC patients, multivariate analysis demonstrated that the percentage of Tex stem was an independent predictor of OS. The median OS for patients with high (above median) Tex stem was significantly longer than those with low Tex stem (9.9 vs 3.4 months, HR 0.398, p = 0.020). In addition, the ratio of Tex stem to Tex term also showed a positive association with OS. Similarly, in mesothelioma patients, a greater percentage of Tex stem was associated with longer OS in multivariate analysis (p = 0.049). The median OS for patients with high vs low Tex stem was 33.5 vs 11.1 months (HR 0.302, 95% CI 0.129 – 0.705, p = 0.006). In addition, there was also a positive association between Tex stem to Tex term ratio and OS. Conversely, Tex term CD8+ T cells did not impact OS in either cancer type. Conclusions: NSCLC and mesothelioma patients with greater abundance of pleural effusion stem-like exhausted CD8+ T cells exhibit better survival outcomes irrespective of patient and disease characteristics, supporting its role as a prognostic biomarker.[Table: see text]
In vivo and in vitro cartilage differentiation from embryonic epicardial progenitor cells
Authors: E Marin Sedeno, P Palmquist-Gomes, GA Rico-Llanos, A Ruiz-Villalba, JM Perez-Pomares, JA Guadix
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Spanish Ministry of Science and Universities and Consejería de Salud y Familias, Junta de Andalucía. The presence of cartilage tissue in embryonic and adult hearts of various vertebrate species is a well-recorded fact. However, while the embryonic neural crest has been historically considered as the main source of cardiac cartilage, recently reported results on the wide connective potential of epicardial lineage cells suggest they could also differentiate into chondrocytes. During heart embryogenesis, the epicardial epithelium forms over the originally bare myocardial surface from epicardial progenitor (proepicardial) cells to then give rise to a large population of mesenchymal Epicardial-Derived Cells (EPDCs) that will crucially contribute to the building, growth and maturation of the ventricle and atrioventricular cardiac structures. In this work, we describe the formation of cardiac cartilage clusters from proepicardial cells, both in vivo and in vitro. Our findings report, for the first time, cartilage formation from epicardial progenitor cells in the embryonic heart, and strongly support the concept of proepicardial cells as multipotent connective progenitors. These results are relevant to our understanding of cardiac cell complexity and responses to pathologic stimuli.
The effect of historical CMV infection on sperm parameters in white-European infertile men: Findings from a real-life cross-sectional study
Authors: F. Belladelli, G. Fallara, E. Pozzi, C. Corsini, M. Raffo, L. Candela, A. Costa, D. Cignoli, N. Schifano, A. D'Arma, P. Capogrosso, L. Boeri, E. Ventimiglia, R. Matloob, L. Pagliardini, F. Montorsi, A. Salonia
Journal: European Urology (2022)
Correlates of common concerns in older cancer survivors of leukemia and lymphoma: Results from the WHI-LILAC study.
Authors: Kah Poh Loh, Eric McLaughlin, Jessica L. Krok-Schoen, Lisa Johnson, Oreofe Olukemi Odejide, Areej El-Jawahri, Lihong Qi, Aladdin H. Shadyab, Electra D. Paskett
Journal: Journal of Clinical Oncology (2022)

e24031 Background: Older survivors of leukemia and lymphoma often experience long-term and late effects of chemotherapy, worsened by aging-related conditions such as functional and cognitive impairment, which may be inadequately addressed. In this study, we described common concerns in older survivors of leukemia and lymphoma, and assessed demographic and clinical factors associated with these concerns. Methods: We utilized data from the WHI LILAC study that recruited post-menopausal women aged 50 and 79 years. Participants who were diagnosed with leukemia and lymphoma after enrollment in WHI and answered at least half of the questions on current concerns in LILAC were included (n = 420). Participants were asked about 14 areas of current concerns common in cancer survivorship and to rate each from 0 (no concern) to 2 (major concern), with total score ranging 0-28. Linear regression was used to assess demographic and clinical factors associated with the concern score, and logistic regression for factors associated with the three most common concerns, with backward variable selection methods. Results: Mean age at assessment was 81 years (range 69-99) and 73% had non-Hodgkin lymphomas. Median time since diagnosis was 8.8 years (range 2.5-20.8 years). Seventy-two percent reported any concern; median concern score among these survivors was 3.5 (Q1-Q3, 2-5) (Table). Factors significantly correlated with the concern score were sadness, pain, loneliness, worse quality of life (QoL), lower physical functioning, more comorbidities, and greater prior symptom count (all p &lt; 0.05). Significant factors correlated with common concerns were: 1) Fatigue/sleep: leukemia diagnosis, greater prior symptom count, feeling sad or depressed, reported distress, lower physical functioning; 2) Physical functioning/activity: public health insurance, older age, greater prior symptom count, reported pain, worse QoL, higher BMI; 3) Memory/concentration: prior chemotherapy or radiation, loneliness, worse QoL, greater prior symptom count (all p &lt; 0.05). Conclusions: Almost three-quarter of survivors of leukemia and lymphoma reported at least one concern, with common concerns being fatigue/sleep, physical functioning/activity, and memory/concentration. A multicomponent intervention is needed to address these common concerns in older cancer survivors.[Table: see text]
Trial in progress: A phase I trial of dual EZH 1/2 inhibitor valemetostat tosylate (DS-3201b) in pediatric, adolescent, and young adult patients with malignant solid tumors.
Authors: Ayumu Arakawa, Hitoshi Ozawa, Akihiro Hirakawa, Ryo Sadachi, Yukari Hoshina, Sawako Tomatsuri, Yoshimasa Saito, Reiko Makihara Ando, Keita Terashima, Kenichi Nakamura, Chitose Ogawa
Journal: Journal of Clinical Oncology (2022)

TPS10059 Background: Enhancer of zeste homolog enzymes (EZH1 and EZH2) form parts of the polycomb repressive complex 2 and regulate gene expression by catalyzing the tri-methylation of lysine 27 residue of histone H3. SMARCB1/INI1 is one of the core components of the SWI/SNF chromatin remodeling complex, with the loss of SMARCB1/INI1 causing the oncogenic activation of EZH2 and EZH1. The inhibition of EZH2 or both EZH2 and EZH1 can be effective against various hematological malignancies and SMARCB1/INI1-deficient solid tumors. Valemetostat tosylate (DS-3201b; valemetostat) is a potential first-in-class dual inhibitor of EZH1 and EZH2 that targets epigenetic regulations by inhibiting both EZH1 and EZH2 enzymes. A phase 2 single-arm study showed that valemetostat demonstrated promising response rates in Japanese patients with relapsed or refractory adult T-cell leukemia/lymphoma (Yoshimitsu M et al., presented at ASH Annual Meeting, 2021). Tumors characterized by SMARCB1/INI1 deficiency (a SWI/SNF mutation), such as malignant rhabdoid tumors, epithelioid sarcoma, or synovial sarcoma are quite frequently observed during childhood and adolescence, among whom valemetostat is expected to show antitumor effects. Methods: This open-label multi-center phase I trial evaluates the safety and efficacy of valemetostat in pediatric, adolescent, and young adult patients with refractory/relapsed solid tumors. The inclusion criteria are relapsed, refractory, or progressive metastatic disease; &gt;3 and &lt;19 years of age during the dose escalation cohort and &lt; 29 years of age in the expanded cohort; performance status of &gt;50 (assessed by Karnofsky Performance score in patients &gt;16 years old, and Lansky Performance score in patients &lt;15 years old); and adequate organ function. Valemetostat is administered orally once a day without interruption. Three dose levels (150, 200, and 250 mg/1.7 m 2 ) are assessed using a 3+3 design during the dose escalation cohort. After determining the recommended phase 2 dose (RP2D) during dose escalation cohort, up to 30 patients will be further enrolled, and the safety and efficacy data of valemetostat are determined in the expanded cohort. The primary endpoint is the incidence of dose limiting toxicity, whereas the secondary endpoints include safety, pharmacokinetics, overall response rate, progression-free survival. The overall response rate of the tumors with SMARCB1/INI1 deficiency or SWI/SNF mutation is also evaluated as a secondary endpoint. Exploratory endpoint includes overall survival. Enrollment into this trial began in March 2020, and enrollment into the dose escalation cohort was completed. Enrollment into the expanded cohort began in November 2021. Clinical Trial Information: jRCT2031190268.
The Timing of Cancer Drug Approvals in the United States and Europe
Authors: Kristina Jenei
Journal: JAMA Network Open (2022)

Mark P. Lythgoe, MBBS; Aakash Desai, MBBS; Bishal Gyawali, MD, PhD; Philip Savage, MD; Jonathan Krell, PhD; Jeremy L. Warner, MD, MS; Ali Raza Khaki, MD, MS
Safety and clinical activity of belantamab mafodotin with pembrolizumab in patients with relapsed/refractory multiple myeloma (RRMM): DREAMM-4 Study.
Authors: Attaya Suvannasankha, Nizar J. Bahlis, Suzanne Trudel, Katja Weisel, Christian Koenecke, Albert Oriol Rocafiguera, Peter M. Voorhees, Aránzazu Alonso Alonso, Natalie Scott Callander, Maria-Victoria Mateos, Nishitha Reddy, Shawn Hakim, Nashita Patel, Danae Williams, Roxanne C. Jewell, Xiangdong Zhou, Ira V. Gupta, Ajay K. Nooka
Journal: Journal of Clinical Oncology (2022)

8018 Background: Belantamab mafodotin (belamaf; BLENREP), a B-cell maturation antigen (BCMA) targeted antibody–drug conjugate approved for adult patients with RRMM, has a multimodal mechanism that eliminates myeloma cells via direct cytotoxicity and a systemic anti-tumor immune response, which may be augmented by an immune checkpoint inhibitor. DREAMM-4 (NCT03848845) assessed safety and clinical activity of belamaf with pembrolizumab (pembro) in RRMM. Methods: This was a Phase I/II, single-arm, open-label study of adults with RRMM after ≥3 lines of therapy (LOT, including anti-CD38 monoclonal antibody, proteasome inhibitor, and immunomodulator). Part 1 established the dose of belamaf 2.5 mg/kg with pembro 200 mg, both IV Q3W up to 35 cycles, for the Part 2 expansion. Primary efficacy endpoint was investigator-assessed overall response rate (ORR, ≥partial response [PR] per IMWG criteria by investigator). Secondary endpoints included duration of response (DoR), progression-free survival (PFS), adverse events (AEs) per NCI-CTCAE v4.03, and pharmacokinetics (PK). Results: This primary analysis of all treated pts (as of Oct 18, 2021) included 34 pts (6 in Part 1 and 28 in Part 2). In both parts, median prior LOT was 5 (range 3–13); 10 pts (29%) had high-risk cytogenetics and 9 (26%) had extramedullary disease. ORR was 47%, with most responses (10/16 pts) ≥ very good PR (VGPR, Table). Median follow-up was 14.7 months (mo); median (95% CI) DoR was 8.0 (2.1–not reached) mo; median PFS was 3.4 (1.4–5.6) mo. Most pts had ≥1 AE (any grade [Gr]: 97%; Gr ≥3: 74%) and treatment-related AE (TRAE, any Gr: 97%; Gr ≥3: 65%). Most common (≥35%) AEs were keratopathy (any Gr: 76%; Gr ≥3: 38%), vision blurred (any Gr: 38%; Gr ≥3: 0%), and thrombocytopenia (any Gr: 35%; Gr ≥3: 29%). AEs led to dose delays (65%) and dose reductions (32%), but not discontinuation. Nine pts had a serious AE (SAE); 4 pts had ≥1 SAE related to study treatment. Two pts had immune-related AEs of Gr 1 (gout and autoimmune hypothyroidism). Preliminary PK and soluble BCMA data were consistent with single-agent belamaf therapy. Conclusions: Belamaf + pembro demonstrated a favorable ORR compared with single-agent belamaf in heavily pre-treated RRMM. No new TRAEs were identified; AE frequency and severity were similar to single-agent belamaf. Correlative biomarker studies are ongoing. Clinical trial information: NCT03848845. [Table: see text]
LINC-03. A single center retrospective analysis of current therapy and outcome of central nervous system tumors in children of Beijing
Authors: Miao Li, Shuxu Du, Yanling Sun, Xiaojun Gong, Jingjing Liu, Siqi Ren, Jin Zhang, Wenchao Gao, Shuting Li, Lulu Wan, Yuan Wang, Yuefang Wu, Yan Liu, Zhen Zhang, Hong Tang, Wanshui Wu, Liming Sun
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVE: To explore the clinical characteristics, therapy and outcome in children with central nervous system (CNS) tumors in Beijing, China. METHODS: Clinical data of 1003 patients with newly diagnosed CNS tumors under the age of 15 years admitted to Beijing Shijitan Hospital between January 2017 and December 2021 were retrospectively analyzed. The diagnoses were confirmed by pathology and/or molecular tests. RESULTS: 34 patients were lost to follow up. Medulloblastoma (n=472), ependymoma (n=79), ETMR (n=59) and pinealoblastoma (n=19) were treated according to HIT-2000/2017, 5-year progression-free survival (PFS) and overall survival (OS) were 76.4 ± 2.3%/ 84.8 ±1.9% in MB, 88.8±3.7% /89.5±3.8% in ependymoma, 49.9±7.6%/59.6±10.7% in ETMR, and 3y-PFS/OS of 11.1±10.5%, 90.0±9.5% in pinealoblastoma. The detailed histology of 59 cases of embryonal tumors included 40 cases of CNS embryonal tumor, 9 neuroblastoma, 7 ETMR, and 3 rare tumors (Intracranial mesenchymal tumor with FET-CREB fusion, CNS high-grade neuroepithelial tumor with BCOR alteration, and Melanotic neuroectodermal tumor of infancy). Among 19 cases of pinealoblastoma, two contain DICER1 mutations. Atypical teratoid/rhabdoid tumors (n=36) were treated by EU-RHAB-Protocol with 3y-PFS/OS of 42.2 ± 9.4 % and 62.8 ± 9.5 %. For low-grade gliomas (n=153, 114 cases of OPG and 39 other non-STR/NTR or progressive cases) under SIOP-LGG 2004, 5y-PFS/OS rates were 77.6±5.2% and 92.4±3.2%; Comparatively, among 63 cases of high-grade gliomas, 19 cases survived with median survival of 52 months, 44 cases died. Choroid plexus cancers (n=13) were treated according to CPT-SIOP-2009 with 5y-PFS /OS of 68.4 ± 13.1 % and 64.8±14.3 %. Among 109 germ cell tumors, 5y-PFS/OS were 93.8±2.8% and 95.5±2.2%, respectively. CONCLUSION: The prognosis of CNS tumors are related to pathology, molecular type and individualized therapy. By international multicenter cooperation and adopting advanced protocols, the survival rates of pediatric CNS tumors can be significantly improved.
Engaging continuing medical education in evaluating knowledge gaps and preferences in advanced BRAF+ melanoma.
Authors: Katie Robinson, Jillian L Scavone, Emily Scully, Emily Lewis, Robert A. Esgro, John M. Kirkwood
Journal: Journal of Clinical Oncology (2022)

e23007 Background: Given the rapid evolution of treatments for advanced melanoma, oncology providers are challenged to stay current on evidence-based recommendations for optimal patient care. Integrating practice-based polling into continuing medical education (CME) activities is a proven way to increase engagement, address knowledge gaps, and assess attitudes on specific topics. Methods: We provided a CME activity designed to educate oncology and dermatology providers on the latest advances regarding the management of advanced BRAFmut+ melanoma. Interspersed engagement opportunities further assessed practice preferences and elucidated persisting educational needs. The CE activity was available for credit from December 31, 2020 to December 30, 2021. Results: 305 medical oncology or dermatology providers who each see an average of 25 patients with melanoma per month participated. These providers scored an average 38% on pretest topics related to the use of triple therapy and patient and/or tumor characteristics that guide clinical decision-making. Post-learning, providers scored 84%, highlighting the impact of the education on knowledge gaps. Notably, while 51% of these providers indicated that they were guessing on the pre-test, the percentage of those who were confident and correct on the post-test rose from 3% to 28%, demonstrating a rise in confidence among participants. While 50% of participants noted a positive perception of triple therapy (BRAF inhibitor + MEK inhibitor + anti-PD1) in the front-line setting, case-based polling questions showed that providers lack consensus regarding the use of combinations of treatments in other clinical scenarios. While 45% would recommend triple therapy in the first-line setting, dual checkpoint inhibitor (CPI)-based treatment is preferred after progression on a first-line CPI or dual-targeted therapy. Conclusions: CME is a useful method to address knowledge gaps regarding evolving treatment options. As data regarding the use of triple therapy for patients with BRAF+ melanoma emerges, oncology and dermatology providers will require further education on how to apply these options in practice.[Table: see text]
Retrospective study to estimate the prevalence of HER2-low breast cancer (BC) and describe its clinicopathological characteristics.
Authors: Giuseppe Viale, Naoki Niikura, Eriko Tokunaga, Olga Aleynikova, Naoki Hayashi, Joohyuk Sohn, Ciara O'Brien, Gavin Higgins, Della Varghese, Gareth D James, Akira Moh, Nana Scotto
Journal: Journal of Clinical Oncology (2022)

1087 Background: Approximately 50% of BCs traditionally categorized as HER2 negative (HER2-neg) express low levels of HER2 (IHC 1+ or IHC 2+/ISH-; Miglietta, NPJ Breast Cancer 2021). HER2-targeted therapies for HER2-low metastatic BC (mBC) are under investigation (eg, T-DXd in the phase 3 DESTINY-Breast04 study; NCT03734029), but HER2 assays currently used to select patients (pts) for approved anti-HER2 therapies are optimized for high HER2 expression and are not validated for HER2-low detection. A recent study found relatively poor agreement (&lt;70% interrater agreement) in evaluation of IHC scores of 0 and 1+ using current HER2 assays (Fernandez, JAMA Oncol 2022). Our objectives were to assess the prevalence of HER2-low among HER2-neg based on rescored HER2 IHC slides after training on low-end expression scoring and to describe pt characteristics of HER2-low vs HER2 IHC 0 mBC. Preliminary results are reported for 233 of 1000 planned pts. Methods: This multicenter, retrospective study (NCT04807595) included pts with confirmed HER2-neg unresectable/mBC diagnosed between 2015 and 2017. Local laboratories, blinded to historical HER2 scores, rescored HER2 IHC-stained slides. HER2 was assessed using Ventana 4B5 and other assays. BCs were categorized as HER2-low or HER2 IHC 0. The prevalence of HER2-low BC among pts originally scored as HER2-neg was measured. Demographics (eg, age, country, race) and clinicopathological characteristics were examined via medical charts/electronic health records. Concordance between historical HER2 scores and rescores was assessed. Results: HER2 rescores were obtained for 233 pts (mean age, 54 y). HER2-low prevalence was 63.2% overall and numerically greater in hormone receptor (HR)–positive vs HR-negative subgroups (66.1% vs 54.8%; Table). No notable differences in prevalence were seen among different HER2 assays or in demographic/baseline disease characteristics between the HER2-low and HER2 IHC 0 groups. Concordance rate between historical and rescored slides for HER2-status classification was 82.3%. The presentation will include an expanded data set (≈400 pts) with additional results. Conclusions: Data on HER2-low prevalence in BC is limited. Preliminary data from this study of mBC samples suggest a somewhat higher prevalence estimate (≈63%) than a previous study of primary BC samples (≈50%). Concordance was 82%; ongoing analyses with updated data will clarify the concordance between rescored and historical HER2 slides. These data can support development of best practices for identifying pts with HER2-low expression who may benefit from HER2-targeted therapies. Clinical trial information: NCT04807595. [Table: see text]
Long-term outcomes and late toxicity of adult medulloblastoma treated with combined modality therapy: A contemporary single-institution experience
Authors: Anurag Saraf, Torunn I Yock, Andrzej Niemierko, Kevin S Oh, William T Curry, William E Butler, Deborah A Forst, Isabel Arrillaga-Romany, David H Ebb, Nancy J Tarbell, Shannon MacDonald, Jay S Loeffler, Helen A Shih
Journal: Neuro-Oncology (2022)

Abstract Background Medulloblastoma (MB) is a rare central nervous system malignancy of adults, with limited contemporary studies to define treatment guidelines and expected late toxicity. Methods A single-center, retrospective study was conducted of patients age ≥18 years from 1997–2019 with MB and who were treated with postoperative radiotherapy. Late toxicity was defined as a minimum of 18 months from diagnosis. Overall survival (OS) and progression-free survival (PFS) were characterized using Kaplan-Meier and Cox regression analyses. Results Fifty-nine patients met criteria, with median age of 25 years (range 18–62 y) and median follow-up of 6.5 years (range 0.7–23.1 y). At diagnosis, 68% were standard-risk, 88% Chang M0, and 22% with anaplastic histology. Gross total resection was achieved in 75%; median craniospinal irradiation dose was 30.6 Gy (relative biological effectiveness [RBE]), median total dose was 54.0 Gy (RBE), 80% received proton radiotherapy; 81% received chemotherapy. 5 year PFS and OS were 86.5% and 95.8%, respectively; 10 year PFS and OS were 83.9% and 90.7%, respectively. Anaplastic histology was associated with worse PFS (P = .04). Among eight recurrences, 25% presented after 5 years. Most common grade ≥2 late toxicities were anxiety/depressive symptoms (30%), motor dysfunction (25%), and ototoxicity (22%). Higher posterior fossa radiation dose was associated with increased risk of late toxicity, including worse cognitive dysfunction (P = .05). Conclusions Adults with MB have favorable survival outcomes, but late failures and toxicity are not uncommon. Better understanding of prognostic factors, possibly from molecular subtyping, may help to define more personalized treatments for patients with high risk of recurrence and long-term treatment sequelae.